title: Selectivity and potency of the retroprogesterone dydrogesterone in vitro.
abstract: Dydrogesterone is widely used for menstrual disorders, endometriosis, threatened and habitual abortion and postmenopausal hormone replacement therapy. Although progestins have a promiscuous nature, dydrogesterone does not have clinically relevant androgenic, estrogenic, glucocorticoid or mineralocorticoid activities. To date, systematic biochemical characterization of this progestin and its active main metabolite, 20α-dihydrodydrogesterone, has not been performed in comparison to progesterone. The objective of this study was to evaluate the selectivity and potential androgenic/antiandrogenic effects of dydrogesterone and its metabolite in comparison to progesterone and medroxyprogesterone acetate by analyzing their interference with AR signaling in vitro. We characterized dydrogesterone and its metabolite for their binding and transactivation of androgen and other steroid hormone receptors and for their potential inhibitory effects against androgen biosynthetic enzymes, 17β-hydroxysteroid dehydrogenase types 3 and 5 and 5α-reductase types 1 and 2. We found that dydrogesterone resembled progesterone mainly in its progestogenic effects and less in its androgenic, anti-androgenic, glucocorticoid and antiglucocorticoid effects; whereas, 20α-dihydrodydrogesterone showed reduced progestogenic potency with no androgenic, glucocorticoid and mineralocorticoid effects. Effects on the androgen and glucocorticoid receptor differed depending on the technology used to investigate transactivation. Progesterone, but not dydrogesterone and 20α-dihydrodydrogesterone, exerted anti-androgenic effects at the pre-receptor level by inhibiting 5α-reductase type 2. Dydrogesterone, 20α-dihydrodydrogesterone and progesterone inhibited the biosynthesis of testosterone catalyzed by 17β-hydroxysteroid dehydrogenase types 3 and 5; however, due to their micromolar K(i) values, these activities appeared to be not of relevance at therapeutic levels. Overall, our data show that the anti-androgenic potential of dydrogesterone and 20α-dihydrodydrogesterone is less pronounced compared to progesterone.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: Tea Lanišnik
authors.initials: TL
authors.lastname: Rižner
authors.forename: Petra
authors.initials: P
authors.lastname: Brožič
authors.forename: Christopher
authors.initials: C
authors.lastname: Doucette
authors.forename: Tammy
authors.initials: T
authors.lastname: Turek-Etienne
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Vieira
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.forename: Bart
authors.initials: B
authors.lastname: van der Burg
authors.forename: Christiane
authors.initials: C
authors.lastname: Böcker
authors.forename: Bettina
authors.initials: B
authors.lastname: Husen
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D004394:Dydrogesterone / Q000031:analogs & derivatives / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011372:Progestins / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C514239:20-alpha-dihydrodydrogesterone; D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D047628:Estrogen Receptor alpha; D011372:Progestins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D004394:Dydrogesterone; D015067:17-Hydroxysteroid Dehydrogenases